A. Field of the Invention
This invention relates to stable lyophilized formulations of canfosfamide and their preparation.
B. Description of the Related Art
McIntyre and Castañer, “Canfosfamide Hydrochloride”, Drugs Fut., 29(10), 985-991 (2004), describe canfosfamide hydrochloride (USAN), a phosphorodiamidate anticancer agent activated by glutathione S-transferase P1-1. The article also identifies canfosfamide hydrochloride with the codes TER-286 and TLK-286.
Morgan et al., “Tumor Efficacy and Bone Marrow-sparing Properties of TER286, a Cytotoxin Activated by Glutathione S-Transferase”, Cancer Research, 58(12), 2568-2575 (1998) describe preclinical studies on canfosfamide hydrochloride, including animal studies. According to the article, “for some studies, it was prepared in 60 mM sodium citrate for i.v. delivery.”
Tew et al., “TLK-286: a novel glutathione S-transferase-activated prodrug”, Expert Opin. Investig. Drugs, 14(8), 1047-1054 (2005), note that “The formulation of TLK-286 in vials containing 265 mg of the sterile lyophilized drug permits solubilization in water for injection to a concentration of 50 mg/ml, followed by dilution to the appropriate dose in 5% dextrose for injection.”
The disclosures of the documents referred to in this application are incorporated into this application by reference.
Canfosfamide is a very reactive alkylating agent. Given its reactivity, stable formulations of this compounds have been difficult to develop. Aqueous solutions form only in a narrow range of pH in which the drug is soluble. However, such aqueous formulations are stable for perhaps 6 to 12 hours before decomposition products are observed. Moreover, the reactivity of canfosfamide has made it difficult to find formulation excipients which are stable with the drug.